Journal
JOURNAL OF IMMUNOLOGY
Volume 165, Issue 10, Pages 5720-5728Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.165.10.5720
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Funding
- FIC NIH HHS [TW00970-02] Funding Source: Medline
- NIAID NIH HHS [AI 41158-01] Funding Source: Medline
- NIDDK NIH HHS [P30 DK50306] Funding Source: Medline
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The NF-kappaB family of transcription factors are involved in the regulation of innate and adaptive immune functions associated with resistance to infection. To assess the role of NF-kappaB(2) in the regulation of cell-mediated immunity, mice deficient in the NF-kappaB(2) gene (NF-kappaB(2)(-/-)) were challenged with the intracellular parasite Toxoplasma gondii, Resistance to this opportunistic pathogen Is dependent on the production of IL-12, which is required for the development of innate NK cell and adaptive T cell responses dominated by the production of IFN-gamma necessary to control replication of this parasite. Although mild-type controls were resistant to T.gondii, NF-kappaB(2)(-/-) mice developed severe toxoplasmic encephalitis and succumbed to disease between 3 and 10 wk following infection. However, NF-kappaB(2) was not required for the ability of macrophages to produce IL-12 or to inhibit parasite replication and during the acute stage of infection, NF-kappaB(2)(-/-) mice had no defect in their ability to produce IL-12 or IFN-gamma and infection-induced NK cell responses appeared normal. In contrast, during the chronic phase of the infection, susceptibility of NF-kappaB(2)(-/-) mice to toxoplasmic encephalitis was associated with a reduced capacity of their splenocytes to produce IFN-gamma associated with a loss of CD4(+) and CD8(+) T cells, This loss of T cells correlated with increased levels of apoptosis and with elevated expression of the pro-apoptotic molecule Fas by T cells from infected NF-kappaB(2)(-/-) mice. Together, these results suggest a role for NF-kappaB(2)(-/-) in the regulation of lymphocyte apoptosis and a unique role for this transcription factor in maintenance of T cell responses required for long-term resistance to T. gondii.
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